Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers

Joan Miguel Romero; Emma Titmuss; Yifan Wang; James Vafiadis; Alain Pacis; Gun Ho Jang; Amy Zhang; Bryn Golesworthy; Tatiana Lenko; Laura M Williamson; Barbara Grünwald; Grainne M O'Kane; Steven J M Jones; Marco A Marra; Julie M Wilson; Steven Gallinger; Janessa Laskin; George Zogopoulos

doi:10.1038/s41698-023-00428-2

Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers

NPJ Precis Oncol. 2023 Aug 9;7(1):73. doi: 10.1038/s41698-023-00428-2.

Authors

Joan Miguel Romero^{1

2}, Emma Titmuss³, Yifan Wang^{1

2

4}, James Vafiadis^{1

2}, Alain Pacis^{2

5}, Gun Ho Jang⁶, Amy Zhang⁶, Bryn Golesworthy^{1

2}, Tatiana Lenko^{1

2}, Laura M Williamson³, Barbara Grünwald⁷, Grainne M O'Kane^{6

8}, Steven J M Jones⁹, Marco A Marra⁹, Julie M Wilson⁶, Steven Gallinger^{6

8}, Janessa Laskin¹⁰, George Zogopoulos^{11

12

13

14}

Affiliations

¹ Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
² Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada.
³ Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada.
⁴ Department of Surgery, McGill University, Montréal, QC, Canada.
⁵ Canadian Centre for Computational Genomics, McGill University and Genome Québec Innovation Centre, Montréal, QC, Canada.
⁶ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁷ Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁸ Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁹ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada.
¹¹ Research Institute of the McGill University Health Centre, Montréal, QC, Canada. george.zogopoulos@mcgill.ca.
¹² Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada. george.zogopoulos@mcgill.ca.
¹³ Department of Surgery, McGill University, Montréal, QC, Canada. george.zogopoulos@mcgill.ca.
¹⁴ Department of Oncology, McGill University, Montréal, QC, Canada. george.zogopoulos@mcgill.ca.

Abstract

Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Score^hi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Score^hi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Score^hi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22-0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.